Tissue-specific Glucocorticoid Signaling May Determine the Resistance Against Glucocorticoids in Autoimmune Diseases

Abstract

Endogenous glucocorticoids exert a diverse array of physiological processes including immune-modulatory or anti-inflammatory responses and play an important role in the pathogenesis of inflammatory and autoimmune diseases. Regulation of inflammatory processes by glucocorticoids is controlled in a cytokine-hypothalamo-pituitary-adrenal axis feedback circuit and on the local, cell-type and context-specific local regulatory system. At the tissue level the sensitivity and response to glucocorticoids are determined by multiple factors: including the local availability to glucocorticoids transported by blood, the locally-formed bioactive glucocorticoids (synthesized and metabolized 11β-hydroxysteroid dehydrogenase enzymes), the number and function of the glucocorticoid receptor (GR) and the GR affinity to its ligands. Numerous molecular factors are known to influence the sensitivity of glucocorticoid response through the GR. Cytokines are one of the major components that can inhibit GR function and can potentiate the resistance against glucocorticoids. GR isoforms, generated by alternative splicing, alternative translation and post-translation modification are further mechanisms which modulate glucocorticoid signaling. Genetic variants within the GR encoding gene are other potential factors that may influence the susceptibility and severity of autoimmune disorders and may play a key role in individual response to medication. In this review our aim was to summarize our knowledge about the connections between the cell type-specific glucocorticoid signaling and the local immune system. Prediction of individual sensitivity to steroids and identification of key players in development of glucocorticoid resistance are essential in individualized therapies. The local, tissue-specific glucocorticoid signaling and its influence by cytokines may be important in determining the magnitude of inflammatory reactions, and may also be related to the success of glucocorticoid-containing therapeutic strategies.